The effect of growth hormone (GH) replacement on blood glucose homeostasis in adult nondiabetic patients with GH deficiency: real-life data from the NordiNet® International Outcome Study.

OBJECTIVE: To assess the effect of 4 years' growth hormone (GH) replacement on glucose homeostasis and evaluate factors affecting glycosylated haemoglobin (HbA1c ) in adults with growth hormone deficiency (GHD). DESIGN: NordiNet® International Outcome Study, a noninterventional study, monitors long-term effectiveness and safety of GH replacement [Norditropin® (somatropin), Novo Nordisk A/S] in real-life clinical practice. PATIENTS: Nondiabetic patients (n = 245) with adult-onset GHD (age ≥20 years at GH start), ≥4 years' GH replacement and HbA1c values at baseline and 4 years were included in the analysis. MEASUREMENTS: Changes from baseline (∆) to 4 years in HbA1c , fasting plasma glucose (FPG), IGF-I, lipids (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglycerides), waist circumference, glycaemic (HbA1c <5·7%; HbA1c , 5·7-6·5%; HbA1c , ≥6·5%) and metabolic health status were evaluated. Effects of baseline HbA1c , gender, baseline age, average GH dose and baseline body mass index (BMI) on ΔHbA1c were investigated. The models were adjusted for concomitant medication use. RESULTS: Mean (standard deviation) baseline HbA1c was 5·13 (0·65)% and remained at the same level at 4 years. Age at treatment start (P = 0·0094) and BMI (P = 0·0008) had a significant impact on ∆HbA1c . At 4 years, 85% of patients with HbA1c <5·7% (normal levels) at baseline and 55% of patients with HbA1c 5·7-6·5% (impaired glucose tolerance) at baseline remained in the same glycaemic health category. Nineteen patients improved from impaired glucose tolerance to normal HbA1c . Seven patients developed diabetes. CONCLUSIONS: These data demonstrate that 4 years' GH replacement therapy did not adversely affect glucose homeostasis in the majority of adults with GHD.

Association of parental history of type 2 diabetes with age, lifestyle, anthropometric factors, and clinical severity at type 2 diabetes diagnosis: results from the DD2 study.

BACKGROUND: We investigated whether parental history of type 2 diabetes mellitus (T2D) is associated with age, lifestyle, anthropometric factors, and clinical severity at the time of T2D diagnosis. METHODS: We conducted a cross-sectional study based on the Danish Centre for Strategic Research in Type 2 Diabetes cohort. We examined the prevalence ratios (PR) of demographic, lifestyle, anthropometric, and clinical factors according to parental history, using Poisson regression adjusting for age and gender. RESULTS: Of 2825 T2D patients, 34% (n = 964) had a parental history of T2D. Parental history was associated with younger age at diagnosis [adjusted (a)PR 1.66, 95% confidence interval: 1.19, 2.31) for age <40 years; aPR 1.36 (95% confidence interval: 1.24, 1.48) for ages 40-59 years] and with higher baseline fasting plasma glucose [≥7.5 mmol/L, aPR 1.47 (95% confidence interval: 1.20, 1.80)], and also tended to be associated with lower beta cell function. In contrast, patients both with and without a parental history had similar occurrence of central obesity [91% vs. 91%], weight gain ≥30 kg since age 20 [52% vs. 53%], and lack of regular physical activity [60% vs. 58%]. Presence of diabetes complications or comorbidities at T2D diagnosis was not associated with parental history. CONCLUSIONS: The lack of an association between parental history and adverse lifestyle factors indicates that T2D patients do not inherit a particular propensity for overeating or inactivity, whereas patients with a parental history may have more severe pancreatic beta cell dysfunction at diagnosis.

Growth hormone replacement does not increase mortality in patients with childhood-onset growth hormone deficiency.

CONTEXT: Long-term safety of growth hormone (GH) treatment is an area of much debate. Studies including children treated with GH not only due to GHD, but also due to non-GHD causes like idiopathic short stature or like short stature in children born small for gestational age have suggested that GH treatment is associated with increased mortality or stroke. OBJECTIVE: To study the impact of GH replacement on overall and cause-specific mortality in childhood-onset GHD (CO GHD) patients. DESIGN: A nationwide population-based registry study on patients with CO GHD and general population controls matched on age and gender. Mortality hazard ratios (HRs) were computed comparing patients and controls, and comparing GH-replaced patients and non-GH-replaced patients, using Cox regression. Comparing GH- and non-GH-replaced patients HRs were adjusted for birth year, year of diagnosis, gender, irradiation, ACTH insufficiency and primary disease. PATIENTS AND CONTROLS: A total of 494 patients with CO GHD each matched with 100 general population controls were included. RESULTS: Mortality was substantially increased comparing patients with CO GHD and general population controls, HR = 7·51 (95% CI = 6·06-9·31). Comparing GH-replaced patients with non-GH-replaced patients mortality was significantly decreased in total (HR = 0·27, CI = 0·17-0·43) and due to malignancy (HR = 0·14, CI = 0·07-0·28) in GH-replaced patients. Adjusting for relevant confounders, this decrease remained significant both in total (HR = 0·56, CI = 0·32-0·96) and due to malignancy (HR = 0·33, CI = 0·16-0·69). Overall and cause-specific mortality was increased in both GH-replaced and non-GH-replaced patients compared to general population controls, but mortality was generally highest in non-GH-replaced patients. CONCLUSION: The present data from a national cohort of patients with CO GHD do not support the suggestion that GH replacement is associated with increased mortality.

Low myocardial glucose uptake in Turner syndrome is unaffected by growth hormone: a randomized, placebo-controlled FDG-PET study.

BACKGROUND: An unfavourable cardiovascular and metabolic phenotype causes threefold excess mortality in Turner syndrome (TS), and perturbed cardiac substrate metabolism is increasingly recognized as a common component of cardiovascular and metabolic diseases. We therefore hypothesized that myocardial glucose uptake (MGU) is reduced in TS and that growth hormone (GH) treatment improves MGU. To this end, this controlled trial elucidates MGU in TS and the impact of 6 months of growth hormone treatment on MGU. METHODS AND RESULTS: Women with TS (n = 9) were examined at baseline, sequentially treated with either Norditropin(®) SimpleXx or placebo and re-examined after 6 months. MGU and myocardial blood flow (MBF) were measured using 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) during a hyperinsulinaemic euglycaemic clamp (at baseline and 6 months). Blood pressure measurement, blood sampling, echocardiography and dual energy X-ray absorptiometry scan were also performed. Age-matched female controls (n = 9) were examined once. Baseline MGU was reduced in TS (0.24 ± 0.08 vs. 0.36 ± 0.13 µmol/g/min in controls; P = 0.036) despite similar insulin sensitivity (whole body glucose uptake (M-value): 9.69 ± 1.86 vs. 9.86 ± 2.58 mg/(min*kg) in controls; P = 0.9). Six months of GH carried no impact on MGU (0.25 ± 0.08 vs. 0.26 ± 0.12 µmol/g/min in the placebo group; P = 0.8). Plasma glucose, low-density cholesterol and triglycerides increased, while M-value and exercise capacity decreased during 6 months of GH treatment. CONCLUSION: MGU is reduced in TS despite normal insulin sensitivity. GH treatment does not alter MGU despite decreased whole body insulin sensitivity. A perturbed cardiac glucose uptake appears to be a feature of TS.

Modifiable clinical and lifestyle factors are associated with elevated alanine aminotransferase levels in newly diagnosed type 2 diabetes patients: results from the nationwide DD2 study.

BACKGROUND: Current literature lacks data on markers of non-alcoholic fatty liver disease (NAFLD) in newly diagnosed type 2 diabetes mellitus (T2DM) patients. We therefore, conducted a cross-sectional study to examine modifiable clinical and lifestyle factors associated with elevated alanine aminotransferase (ALT) levels as a marker of NAFLD in new T2DM patients. METHODS: Alanine aminotransferase levels were measured in 1026 incident T2DM patients enrolled in the nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort. We examined prevalence of elevated ALT (>38 IU/L for women and >50 IU/L for men) and calculated prevalence ratios associated with clinical and lifestyle factors using Poisson regression. We examined the association with other biomarkers by linear regression. RESULTS: The median value of ALT was 24 IU/L (interquartile range: 18-32 IU/L) in women and 30 IU/L (interquartile range: 22-41 IU/L) in men. Elevated ALT was found in 16% of incident T2DM patients. The risk of elevated ALT was increased in patients who were <40 years old at diabetes debut [adjusted prevalence ratio (aPR): 1.96, 95% confidence interval (CI): 1.15-3.33], in those with alcohol overuse (>14/>21 drinks per week for women/men) (aPR: 1.60, 95% CI: 1.03-2.50), and in those with no regular physical activity (aPR: 1.42, 95% CI: 1.04-1.93). Obesity and metabolic syndrome per se showed no association with elevated ALT when adjusted for other markers, whereas we found positive associations of ALT with increased C-peptide (ß = 0.14, 95% CI: 0.06-0.21) and fasting blood glucose (ß = 0.07, 95% CI: 0.03-0.11). CONCLUSIONS: Among newly diagnosed T2DM patients, several modifiable clinical and lifestyle factors are independent markers of elevated ALT levels.

Effects of human insulin and insulin aspart preparations on levels of IGF-I, IGFBPs and IGF bioactivity in patients with type 1 diabetes.

BACKGROUND: Insulin aspart (IAsp) and its biphasic preparations BIAsp50 and BIAsp70 (containing 50% and 70% IAsp, respectively) have distinct glucose-lowering properties as compared to human insulin (HI). We investigated whether this affected the circulating IGF-system which depends on the hepatic insulin exposure. METHODS: In a randomized, four-period crossover study, 19 patients with type 1 diabetes received identical doses (0.2 U/kg sc) of IAsp, BIAsp70, BIAsp50 and HI together with a standardized meal. Serum total IGF-I and IGFBP-1 to -3 were measured by immunoassays for nine hours post-prandially. Bioactive IGF was determined by an in-house, cell-based IGF-I receptor kinase activation (KIRA) assay. RESULTS: Despite marked differences in peripheral insulin concentrations and plasma glucose, the four insulin preparations resulted in parallel decreases in IGFBP-1 levels during the first 3 hours, and parallel increases during the last part of the study (3-9 hours). Thus, only minor significances were seen. Insulin aspart and human insulin resulted in a lower area under the curve (AUC) during the first 3 hours as compared to BIAsp70 (p = 0.009), and overall, human insulin resulted in a lower IGFBP-1 AUC than BIAsp70 (p = 0.025). Nevertheless, responses and AUCs of bioactive IGF were similar for all four insulin preparations. Changes in levels of bioactive IGF were inversely correlated to those of IGFBP-1, increasing during the first 3 hours, whereafter levels declined (-0.83 ≤ r ≤ -0.30; all p-values <0.05).Total IGF-I and IGFBP-3 remained stable during the 9 hours, whereas IGFBP-2 changed opposite of IGFBP-1, increasing after 3-4 hours whereafter levels gradually declined. The four insulin preparations resulted in similar profiles and AUCs of total IGF-I, IGFBP-2 and IGFBP-3. CONCLUSIONS: Despite distinct glucose-lowering properties, the tested insulin preparations had similar effects on IGF-I concentration and IGF bioactivity, IGFBP-2 and IGFBP-3 as compared to HI; only small differences in IGFBP-1 were seen and they did not affect bioactive IGF. Thus, insulin aspart containing preparation behaves as HI in regards to the circulating IGF-system. However, bioactive IGF appeared to be more sensitive to insulin exposure than total IGF-I. The physiological significance of this finding remains to be determined. TRIAL REGISTRATION: NCT00888732.

Lifestyle and clinical factors associated with elevated C-reactive protein among newly diagnosed Type 2 diabetes mellitus patients: a cross-sectional study from the nationwide DD2 cohort.

BACKGROUND: We aimed to examine the prevalence of and modifiable factors associated with elevated C-reactive Protein (CRP), a marker of inflammation, in men and women with newly diagnosed Type 2 Diabetes mellitus (DM) in a population-based setting. METHODS: CRP was measured in 1,037 patients (57% male) with newly diagnosed Type 2 DM included in the prospective nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project. We assessed the prevalence of elevated CRP and calculated relative risks (RR) examining the association of CRP with lifestyle and clinical factors by Poisson regression, stratified by gender. We used linear regression to examine the association of CRP with other biomarkers. RESULTS: The median CRP value was 2.1 mg/L (interquartile range, 1.0 - 4.8 mg/L). In total, 405 out of the 1,037 Type 2 DM patients (40%) had elevated CRP levels (>3.0 mg/L). More women (46%) than men (34%) had elevated CRP. Among women, a lower risk of elevated CRP was observed in patients receiving statins (adjusted RR (aRR) 0.7 (95% confidence interval (CI) 0.6-0.9)), whereas a higher risk was seen in patients with central obesity (aRR 2.3 (95% CI 1.0-5.3)). For men, CRP was primarily elevated among patients with no regular physical activity (aRR 1.5 (95% CI 1.1-1.9)), previous cardiovascular disease (aRR1.5 (95% CI 1.2-1.9) and other comorbidity. For both genders, elevated CRP was 1.4-fold increased in those with weight gain >30 kg since age 20 years. Sensitivity analyses showed consistent results with the full analysis. The linear regression analysis conveyed an association between high CRP and increased fasting blood glucose. CONCLUSIONS: Among newly diagnosed Type 2 DM patients, 40% had elevated CRP levels. Important modifiable risk factors for elevated CRP may vary by gender, and include low physical activity for men and central obesity and absence of statin use for women.

Plasma levels of the arterial wall protein fibulin-1 are associated with carotid-femoral pulse wave velocity: a cross-sectional study.

BACKGROUND: The arterial system in diabetic patients is characterized by generalized non-atherosclerotic alterations in the vascular extracellular matrix causing increased arterial stiffness compared with subjects without diabetes. The underlying pathophysiology remains elusive. The elastin-associated extracellular matrix protein, fibulin-1, was recently found in higher concentrations in the arterial wall and in plasma in patients with long duration type 2 diabetes. Furthermore, plasma fibulin-1 independently predicted total mortality and was associated with pulse pressure, an indirect measure of arterial stiffness. Whether plasma fibulin-1 is associated with arterial stiffness at earlier phases of type 2 diabetes has not been determined. METHODS: In this cross-sectional study, we examined 90 patients with recently diagnosed type 2 diabetes (< 5 years) and 90 gender- and age-matched controls. Plasma fibulin-1 was measured immunochemically. Arterial stiffness was assessed by carotid-femoral Pulse Wave Velocity (PWV). Differences in means were assessed by t-tests. Associations were assessed by multivariate regression analyses. RESULTS: Plasma fibulin-1 levels were lower in the diabetic group compared with the control group, 93 ± 28 vs 106 ± 30 µg/mL, p = 0.005. In unadjusted analysis of the total study sample, plasma fibulin-1 was not associated with PWV, p = 0.46. However, with adjustment for the confounders age, gender, mean blood pressure, heart rate, body mass index, diabetes and glomerular filtration rate, a 10 µg/mL increase in plasma fibulin was associated with 0.09 ± 0.04 m/s increase in PWV, p < 0.05. In subgroup analysis, plasma fibulin-1 was associated with PWV in the diabetes group, (0.16 ± 0.07 m/s increase in PWV per 10 µg/mL increase in plasma fibulin-1, p<0.05), but not controls, ß = 0.021 ± 0.057 m/s per 10 µg/mL, p = 0.70. The association remained significant in the diabetes group after adjustment for covariates, p < 0.05. CONCLUSIONS: Plasma fibulin-1 is independently associated with PWV. Yet, as the plasma level of fibulin-1 was lower in patients with recently diagnosed type 2 diabetes than in healthy controls, plasma fibulin-1 levels are not a simple marker of the degree of arterial stiffening. Further studies are needed to determine the exact role of fibulin-1 in arterial stiffness and cardiovascular risk in patients with type 2 diabetes.

Measurement of free GH and bioactive IGF-I in non-diabetic haemodialysis patients treated with GH for 7 days.

BACKGROUND: End-stage renal failure (ESRF) patients demonstrate augmented growth hormone (GH) secretion, but normal insulin-like growth factor-I (IGF-I) concentrations, indicating a state of GH resistance. To test this hypothesis, we compared the IGF-I response with exogenous GH in haemodialysis patients and healthy controls, with special focus on free GH and bioactive IGF-I. METHODS: Ultrafiltered free GH and total GH were measured in serum collected hourly for 24 h at baseline and after 7 days of recombinant human (rh) GH (50 µg/kg/day) treatment in 11 non-diabetic haemodialysis patients and 10 matched controls. Serum levels of bioactive IGF-I (determined by cell-based IGF-I receptor activation assay), total IGF-I and the GH-binding protein (GHBP) were assayed twice daily. RESULTS: At baseline, patients showed elevated total GH (24 ± 5 versus 9 ± 1 µg/L × h, P < 0.02), free GH (21 ± 5 versus 7 ± 1 µg/L × h, P < 0.02), reduced GHBP (1.5 ± 0.3 versus 2.5 ± 0.2 nmol/L, P < 0.01), high-normal total IGF-I (173 ± 18 versus 135 ± 14 µg/L, P = 0.12) and subnormal bioactive IGF-I (2.1 ± 0.3 versus 2.8 ± 0.2 µg/L, P < 0.05) when compared with controls. After 7 days of rhGH treatment, there was a greater GH increase in the non-diabetic haemodialysis patients than in controls (total GH: 293 ± 33 versus 166 ± 13 µg/L × h, P < 0.001; free GH: 284 ± 40 versus 126 ± 15 µg/L × h, P < 0.001). GHB remained unaffected and total IGF-I increased to the same extent in patients and controls (701 ± 87 versus 572 ± 33 µg/L, P = 0.17), whereas bioactive IGF-I tended to be lower in patients (5.37 ± 0.55 versus 6.63 ± 0.25 µg/L, P < 0.10). When adjusting for the actual increments in plasma GH, the ability of exogenous GH to stimulate bioactive IGF-I levels was reduced by ~50% in ESRF (P < 0.02), whereas the response of total IGF-I remained normal (74%; P= 0.18) CONCLUSIONS: The study demonstrates that ESRF is associated with markedly elevated serum levels of free GH. Furthermore changes in bioactive, but not immunoreactive, IGF-I indicated that the hepatic sensitivity to GH was reduced by 50% in ESRF patients. Clearly, the physiological importance of our observations awaits further studies, but they suggest that changes in total IGF-I may not necessarily reflect changes in the endogenous activity of IGF-I in ESRF patients on GH treatment.

A prospective randomised cross-over study of the effect of insulin analogues and human insulin on the frequency of severe hypoglycaemia in patients with type 1 diabetes and recurrent hypoglycaemia (the HypoAna trial): study rationale and design.

BACKGROUND: Severe hypoglycaemia still represents a significant problem in insulin-treated diabetes. Most patients do not experience severe hypoglycaemia often. However, 20% of patients with type 1 diabetes experience recurrent severe hypoglycaemia corresponding to at least two episodes per year. The effect of insulin analogues on glycaemic control has been documented in large trials, while their effect on the frequency of severe hypoglycaemia is less clear, especially in patients with recurrent severe hypoglycaemia. The HypoAna Trial is designed to investigate whether short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing the occurrence of severe hypoglycaemic episodes in patients with recurrent hypoglycaemia. This paper reports the study design of the HypoAna Trial. METHODS/DESIGN: The study is a Danish two-year investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, cross-over trial investigating the effect of insulin analogues versus human insulin on the frequency of severe hypoglycaemia in subjects with type 1 diabetes. Patients are randomised to treatment with basal-bolus therapy with insulin detemir / insulin aspart or human NPH insulin / human regular insulin in random order. The major inclusion criterion is history of two or more episodes of severe hypoglycaemia in the preceding year. DISCUSSION: In contrast to almost all other studies in this field the HypoAna Trial includes only patients with major problems with hypoglycaemia. The HypoAna Trial will elucidate whether basal-bolus regimen with short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing occurrence of severe hypoglycaemic episodes in hypoglycaemia prone patients with type 1 diabetes. http://www.clinicaltrials.gov: NCT00346996.

OPPORTUNITY™: a large-scale randomized clinical trial of growth hormone in hemodialysis patients.

BACKGROUND: Adult maintenance hemodialysis (MHD) patients experience high mortality and morbidity and poor quality of life (QoL). Markers of protein-energy wasting are associated with these poor outcomes. The OPPORTUNITY™ Trial examined whether recombinant human growth hormone (hGH) reduces mortality in hypoalbuminemic MHD patients. Secondary end points were effects on number of hospitalizations, cardiovascular events, lean body mass (LBM), serum proteins, exercise capacity, QoL and adverse events. METHODS: We performed a randomized, double-blind, placebo-controlled, multicenter multinational trial stratified for diabetic status. Clinically, stable adult MHD patients with serum albumin <4.0 g/dL were randomized to subcutaneous injections of hGH, 20 µg/kg/day, or placebo. Planned treatment duration was 24 months for 2500 patients. The trial was terminated early due to slow recruitment. RESULTS: Seven hundred and twelve patients were randomized until trial termination; 695 patients received at least one dose of trial medication. Mean treatment duration was 20 weeks (no completers). There were no differences between groups in all-cause mortality, cardiovascular morbidity or mortality, serum albumin, LBM, physical exercise capacity or QoL. The hGH group, compared to placebo, displayed a reduction in body weight, total body fat, serum high-sensitivity C-reactive protein and possibly homocysteine and an increase in serum high-density lipoprotein-cholesterol and transferrin levels. CONCLUSIONS: Although the OPPORTUNITY™ Trial was terminated early, treatment with hGH, compared to placebo, improved certain cardiovascular risk factors but did not reduce mortality, cardiovascular events or improve nutritional factors or QoL. The power for showing differences was substantially reduced due to the marked decrease in treatment duration and sample size.

Abnormalities of the major intrathoracic arteries in Turner syndrome as revealed by magnetic resonance imaging.

BACKGROUND: Ectatic aortopathy and arterial abnormalities cause excess morbidity and mortality in Turner syndrome, where a state of vasculopathy seemingly extends into the major head and neck branch arteries. OBJECTIVE: We investigated the prevalence of abnormalities of the major intrathoracic arteries, their interaction with arterial dimensions, and their association with karyotype. DESIGN: Magnetic resonance imaging scans determined the arterial abnormalities as well as head and neck branch artery and aortic dimensions in 99 adult women with Turner syndrome compared with 33 healthy female controls. Echocardiography determined aortic valve morphology. RESULTS: In Turner syndrome, the relative risk of any congenital abnormality was 7.7 (p = 0.003) and 6.7 of ascending aortic dilation (p = 0.02). A bovine aortic arch was seen in both Turner syndrome and controls. Other abnormalities were only encountered in Turner syndrome: elongated transverse aortic arch (47%), bicuspid aortic valve (27%), aortic coarctation (13%), aberrant right subclavian artery (8%), and aortic arch hypoplasia (2%). The innominate and left common carotid arteries were enlarged in Turner syndrome (p < 0.001). Significant associations were first, bicuspid aortic valve with aortic coarctation, elongated transverse aortic arch, and ascending aortic dilation; second, aortic coarctation with elongated aortic arch and descending aortic dilation; third, 45,X with aortic coarctation, elongated transverse aortic arch and ascending aortic dilation; and fourth, branch artery dilation with bicuspid aortic valve, aortic coarctation, elongated transverse aortic arch and 45,X. CONCLUSION: An increased risk of arterial abnormalities, aortic dilation, and enlargement of the branch arteries was found in Turner syndrome without distinct patterns of co-segregation.

Glycemia, lipidemia and systolic left ventricular function evaluated by myocardial strain rate: a tissue Doppler echocardiographic study.

Recent studies have indicated that hyperglycemia and insulin resistance are significantly correlated to left ventricular (LV) long-axis function, and it seems that optimized glycemic control is significantly related to improved LV function. The aim of the study was to investigate the relation between glucose metabolism, lipid levels and LV long-axis function in normal subjects. The study population consisted of 20 unselected male patients, free of medication and without history of cardiac disease. The main outcome measures were LV systolic strain rate in the long-axis plane, examined by tissue Doppler echocardiography and fasting values of plasma glucose, insulin, cholesterol and triglycerides. The mean systolic strain rate was found to correlate significantly to age (r(2) = 0.34, p < 0.01), fasting blood glucose levels (r(2) = 0.25, p < 0.01) and low-density lipoprotein (LDL) cholesterol levels (r(2) = 0.38, p < 0.01). however, did not correlate significantly to traditional measures of insulin resistance like truncal body fat, fasting insulin or triglyceride levels. In conclusion, LV systolic function seems significantly related to fasting levels of glucose and LDL cholesterol in normal subjects.

Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project cohort of newly diagnosed patients with type 2 diabetes: a cohort profile.

PURPOSE: The aim of this article is to provide a detailed description of the ongoing nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project cohort and biobank. The DD2 cohort continuously enrols newly diagnosed patients with type 2 diabetes (T2D) throughout Denmark. The overall goal of the DD2 project is to establish a large and data-rich T2D cohort that can serve as a platform for exhaustive T2D research including (1) improved genotypic and phenotypic characterisation of T2D, (2) intervention studies of more individualised T2D treatment, (3) pharmacoepidemiological studies and (4) long-term follow-up studies on predictors of T2D complications and prognosis. PARTICIPANTS: Between 2010 and 2016, 7011 individuals with T2D have been enrolled and assessed at baseline. Information collected include interview data (eg, body weight at age 20 years, physical activity and alcohol consumption), clinical examination data (eg, hip-waist ratio and resting heart rate) and biological samples (whole blood, DNA, plasma and urine) stored at -80°C and currently analysed for a range of biomarkers and genotypes. FINDINGS TO DATE: Registry linkage has provided extensive supplemental continuous data on glycosylated haemoglobin A, lipids, albuminuria, blood pressure, smoking habits, body mass index, primary care contacts, hospital diagnoses and procedures, medication use, cancer and mortality. Cross-sectional associations between biomarkers, family history, anthropometric and lifestyle measures and presence of complications at baseline have been reported. FUTURE PLANS: During 2016, a detailed follow-up questionnaire has been answered by 85% of initial participants, providing follow-up information on baseline variables and on presence of diabetic neuropathy. The DD2 cohort has now been followed for a total of 18 862 person-years, and nested intervention trials and follow-up studies are ongoing. In the future, the cohort will serve as a strong national and international resource for recruiting patients to nested case studies, clinical trials, postmarketing surveillance, large-scale genome studies and follow-up studies of T2D complications.

Effects of cortisol on carbohydrate, lipid, and protein metabolism: studies of acute cortisol withdrawal in adrenocortical failure.

CONTEXT: Cortisol is an important catabolic hormone, but little is known about the metabolic effects of acute cortisol deficiency. OBJECTIVE: The objective of the study was to test whether clinical symptoms of weight loss, fatigue, and hypoglycemia could be explained by altered energy expenditure, protein metabolism, and insulin sensitivity during cortisol withdrawal in adrenocortical failure. DESIGN, PARTICIPANTS, AND INTERVENTION: We studied seven women after 24-h cortisol withdrawal and during replacement control during a 3-h basal period and a 3-h glucose clamp. RESULTS: Cortisol withdrawal generated cortisol levels close to zero, a 10% decrease in basal energy expenditure, increased TSH and T(3) levels, and increased glucose oxidation. Whole-body glucose and phenylalanine turnover were unaltered, but forearm phenylalanine turnover was increased. During the clamp glucose, infusion rates rose by 70%, glucose oxidation rates increased, and endogenous glucose production decreased. Urinary urea excretion decreased by 40% over the 6-h study period. CONCLUSIONS: Cortisol withdrawal increased insulin sensitivity in terms of increased glucose oxidation and decreased endogenous glucose production; this may induce hypoglycemia in adrenocortical failure. Energy expenditure and urea loss decreased, indicating that weight and muscle loss in Addison's disease is caused by other mechanisms, such as decreased appetite. Increased muscle protein breakdown may amplify the loss of muscle protein.

Quantitative liver functions in Turner syndrome with and without hormone replacement therapy.

BACKGROUND: Studies have documented elevated levels of liver enzymes in many females with Turner syndrome (TS). Histology has shown a range of changes. Treatment with female hormone replacement therapy (HRT) reduces liver enzymes. AIM: To study quantitative liver functions in TS in detail with and without HRT. DESIGN: Randomized crossover study with active treatment (HRT in TS and P-pill in controls) or no treatment. SUBJECTS: Women with TS (n = 8, age 29.7 +/- 5.6 (mean +/- s.d.) years), verified by karyotype, and age-matched controls (C; n = 8, age 27.3 +/- 4.9 years). METHODS: We determined liver enzymes in blood, used the galactose elimination capacity to assess hepatocyte cytosol activity, plasma clearance of indocyanine green to assess excretory function, antipyrine clearance to estimate microsomal activity, and the functional hepatic nitrogen clearance (FHNC) to assess mitochondrial-cytosolic metabolic capacity for conversion of amino-nitrogen. RESULTS: Liver enzymes were elevated in untreated TS and reduced by HRT. The hepatic capacities for conversion of galactose, indocyanine green, and antipyrine were normal and did not change by HRT. The FHNC was marginally reduced (untreated TS vs C: 19.4 +/- 5.4 vs 25.2 +/- 7.3 L/h, P = 0.1). FHNC changed slightly with HRT in TS (19.4 +/- 5.4 vs 24.4 +/- 10.2 L/h, P = 0.2). CONCLUSIONS: The elevations of liver enzymes in untreated TS are readily suppressed by HRT. Quantitative liver functions in TS are comparable to controls and are not affected by HRT.

Effects of growth hormone in patients with tibial fracture: a randomised, double-blind, placebo-controlled clinical trial.

OBJECTIVE: Investigate whether intervention with GH after tibial fracture enhances fracture healing. DESIGN: Randomised, double-blind, placebo-controlled study in 406 patients (93 women, 313 men, age: 18-64 years) with tibial fracture. METHODS: Patients were stratified by tibial fracture (open or closed) and allocated to placebo or GH treatment (15, 30 or 60 mug/kg daily, until clinically assessed healing or until 16 weeks post-surgery). Primary outcome was time from surgery until fracture healing and assessment of healing was done centrally and observer blinded. Patients reported for evaluation every 4 weeks until 24 weeks, and at 9 and 12 months. RESULTS: GH did not accelerate time to healing in the combined group of open and closed fractures. When separately analysing the closed and open fractures, a significant difference in time to healing was observed between treatment groups, exclusively in the closed fractures (P<0.05; subgroup analysis revealed that the 60 microg/kg group was significantly different from placebo). The relative risk of fracture healing for 60 microg/kg versus placebo during the 12 month was: all fractures, 1.16; 95% CI: (0.86; 1.57) (ns); closed fractures, 1.44; 95% CI: (1.01; 2.05; P<0.05); open fractures, 0.75; 95% CI: (0.42; 1.31) (ns). The estimated median number of days before fracture healing in closed fractures was 95 with 60 microg/kg versus 129 with placebo (95% CI: (94; 129) and (94; 249)) corresponding to approximately 26% decrease in healing time. CONCLUSIONS: In the overall group of open and closed tibial fractures, no significant enhancement of fracture healing was observed with GH, whereas in closed tibial fractures, GH accelerated healing significantly.

Mortality and GH deficiency: a nationwide study.

OBJECTIVE: To estimate the mortality in Denmark in patients suffering from GH deficiency (GHD). DESIGN: Mortality was analyzed in 1794 GHD patients and 8014 controls matched on age and gender. All records in GHD patients were studied and additional morbidity noted. Patients were divided into childhood onset (CO) and adult onset (AO), discriminated by an age cutoff below or above 18 years at onset of GHD. METHOD: Data on death were identified in national registries. Sex- and cause-specific mortalities were identified in CO and AO GHD when compared with controls. RESULTS: Mortality was increased in CO and AO GHD in both genders, when compared with controls. The hazard ratio (HR) for CO males was 8.3 (95% confidence interval (CI) 4.5-15.1) and for females 9.4 (CI 4.6-19.4). For AO males, HR was 1.9 (CI 1.7-2.2) and for females 3.4 (CI 2.9-4.0). We found a significantly higher HR in AO females versus AO males, both compared with controls (P < 0.001). In AO, mortality was increased due to cancer in all subgroups, due to circulatory diseases in all age groups for females and for males in the oldest age group. For CO, the increased mortality was due to cancer. CONCLUSIONS: We found a significantly increased mortality in GHD patients when compared with controls, possibly due to their hypopituitary status. Mortality was increased in AO female patients when compared with males. For CO and AO GHD, different causes of significantly increased mortality were identified.

Assessment of hydration by means of bioelectrical impedance and arm muscle area during growth hormone (GH) replacement therapy: A prospective study of 130 GH-deficient patients.

OBJECTIVE: Growth hormone (GH)-deficiency is associated with a reduced extracellular volume (ECV), whereas GH replacement may cause fluid retention. We have tested a simple method to assess hydration in GH-deficient patients (GHD) based on concomitant measurements of body resistance by bioelectrical impedance analysis (BIA), and arm muscle area (AMA). DESIGN: We prospectively followed 130 patients (54 females, 76 males) with adult-onset GHD before and during 1-5 years GH replacement therapy. METHODS: Concomitant measurements of body resistance and AMA were done on four occasions: before treatment, after one month and one year of treatment, and at the most recent visit. Based on normative data obtained in 142 women and 84 men an inverse relationship was documented between body resistance and AMA. Assuming that linear height and the concentration of electrolytes remain constant, body resistance at a given AMA will reflect specific hydration. RESULTS: In the patients a gender-specific inverse correlation between body resistance and AMA existed, which was different from the control group and changed during GH replacement. A deviation between predicted (based on normative data) and measured body resistance at a given AMA was recorded in the patients before and during therapy compatible with relative dehydration in the untreated state followed by an increase in hydration during therapy. CONCLUSIONS: Concomitant measurements of BIA and AMA in GHD patients may provide a non-invasive and simple means to estimate hydration before and during GH replacement.

A phase 2 trial of long-acting TransCon growth hormone in adult GH deficiency.

TransCon growth hormone is a sustained-release human growth hormone prodrug under development in which unmodified growth hormone is transiently linked to a carrier molecule. It is intended as an alternative to daily growth hormone in the treatment of growth hormone deficiency. This was a multi-center, randomized, open-label, active-controlled trial designed to compare the safety (including tolerability and immunogenicity), pharmacokinetics and pharmacodynamics of three doses of weekly TransCon GH to daily growth hormone (Omnitrope). Thirty-seven adult males and females diagnosed with adult growth hormone deficiency and stable on growth hormone replacement therapy for at least 3 months were, following a wash-out period, randomized (regardless of their pre-study dose) to one of three TransCon GH doses (0.02, 0.04 and 0.08 mg GH/kg/week) or Omnitrope 0.04 mg GH/kg/week (divided into 7 equal daily doses) for 4 weeks. Main outcomes evaluated were adverse events, immunogenicity and growth hormone and insulin-like growth factor 1 levels. TransCon GH was well tolerated; fatigue and headache were the most frequent drug-related adverse events and reported in all groups. No lipoatrophy or nodule formation was reported. No anti-growth hormone-binding antibodies were detected. TransCon GH demonstrated a linear, dose-dependent increase in growth hormone exposure without accumulation. Growth hormone maximum serum concentration and insulin-like growth factor 1 exposure were similar after TransCon GH or Omnitrope administered at comparable doses. The results suggest that long-acting TransCon GH has a profile similar to daily growth hormone but with a more convenient dosing regimen. These findings support further TransCon GH development.